RESUMO
OBJECTIVE: We present the rare case of a 21 year old woman with small cell carcinoma of the right ovary of the hypercalcemic type with dramatic response to checkpoint inhibitor. METHODS: Case report. RESULTS AND CONCLUSIONS: Our patient, a 22-year old woman with small cell carcinoma of the hypercalcemic type with hepatic metastases, is currently 43 months under treatment with pembrolizumab. Last MRI revealed no viable liver metastases nor other signs of recurrence. This is the longest survival of a patient with small cell carcinoma of the ovary under therapy with checkpoint inhibitors reported in the literature so far. With this report we emphasize the importance of immunohistological testing for PD-L 1. Treating clinicians should keep off-label use of immune checkpoint blockade in mind when treating this highly aggressive tumor if all other treatment options fail.
Assuntos
Carcinoma de Células Pequenas , Hipercalcemia , Neoplasias Ovarianas , Feminino , Humanos , Adulto Jovem , Adulto , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/patologia , Neoplasias Ovarianas/diagnóstico , Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Hipercalcemia/patologia , Fatores de Transcrição/metabolismoRESUMO
Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
DNA Helicases/deficiência , Proteínas Nucleares/deficiência , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Fatores de Transcrição/deficiência , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Pré-Escolar , DNA Helicases/genética , Feminino , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteína SMARCB1/deficiência , Proteína SMARCB1/genética , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: The development of effective cancer treatments depends on the availability of cell lines that faithfully recapitulate the cancer in question. This study definitively re-assigns the histologic identities of two ovarian cancer cell lines, COV434 (originally described as a granulosa cell tumour) and TOV-112D (originally described as grade 3 endometrioid carcinoma), both of which were recently suggested to represent small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), based on their shared gene expression profiles and sensitivity to EZH2 inhibitors. METHODS: For COV434 and TOV-112D, we re-reviewed the original pathology slides and obtained clinical follow-up on the patients, when available, and performed immunohistochemistry for SMARCA4, SMARCA2 and additional diagnostic markers on the original formalin-fixed, paraffin-embedded (FFPE) clinical material, when available. For COV434, we further performed whole exome sequencing and validated SMARCA4 mutations by Sanger sequencing. We studied the growth of the cell lines at baseline and upon re-expression of SMARCA4 in vitro for both cell lines and evaluated the serum calcium levels in vivo upon injection into immunodeficient mice for COV434 cells. RESULTS: The available morphological, immunohistochemical, genetic, and clinical features indicate COV434 is derived from SCCOHT, and TOV-112D is a dedifferentiated carcinoma. Transplantation of COV434 into mice leads to increased serum calcium level. Re-expression of SMARCA4 in either COV434 and TOV-112D cells suppressed their growth dramatically. CONCLUSIONS: COV434 represents a bona fide SCCOHT cell line. TOV-112D is a dedifferentiated ovarian carcinoma cell line.
Assuntos
Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma de Células Pequenas/diagnóstico , Linhagem Celular Tumoral/patologia , Neoplasias Ovarianas/diagnóstico , Animais , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Desdiferenciação Celular/genética , Linhagem Celular Tumoral/efeitos dos fármacos , DNA Helicases/análise , DNA Helicases/deficiência , DNA Helicases/genética , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Proteínas Nucleares/análise , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fatores de Transcrição/análise , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Sequenciamento do Exoma , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a highly aggressive malignant tumor affecting predominantly young adults and adolescents with an average age of 23.9 at time of diagnosis. Up to two thirds of patients have paraneoplastic hypercalcemia. The molecular signature of these tumors is SMARCA4 mutations, with somatic and germline pathogenic variants previously described. We report a case of a previously healthy one-year-old girl who was noticed to have mild anemia and an abdominal mass during a well-child visit. Further laboratory testing revealed hypercalcemia. A computerized tomography scan showed a left-sided ovarian mass (9.3 x 7.3 x 7 cm). The resection specimen showed a large ovarian tumor with solid tan-yellow cut surfaces and small foci of necrosis. Microscopically, the tumor was composed of sheets of small, hyperchromatic epithelioid cells with focal rhabdoid large cell morphology. The tumor cells were strongly and diffusely positive for WT1 (N-terminal antibodies) with focal EMA and Pan-keratin positivity. Absent SMARCA4 (BRG1) protein expression by immunohistochemistry ultimately established the diagnosis of small cell carcinoma of the ovary, hypercalcemic type. To our knowledge, this is the youngest patient reported in the literature.
Assuntos
Carcinoma de Células Pequenas/diagnóstico , Hipercalcemia/etiologia , Neoplasias Ovarianas/diagnóstico , Síndromes Paraneoplásicas/etiologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/patologia , DNA Helicases/metabolismo , Feminino , Humanos , Hipercalcemia/diagnóstico , Lactente , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Síndromes Paraneoplásicas/diagnóstico , Fatores de Transcrição/metabolismoRESUMO
SCCOHT is an aggressive malignancy linked to alterations of SMARCA4. We describe the diagnosis and therapy of a 32 year old who received multi-agent chemotherapy and underwent a second look operation with HIPEC followed by high-dose chemotherapy with stem cell transplant. Supportive care, oncofertility, and genetic counseling are described.
Assuntos
Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/terapia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/genética , DNA Helicases/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Hipercalcemia/terapia , Quimioterapia Intraperitoneal Hipertérmica , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS) are rare and aggressive tumors, primarily affecting pre- and perimenopausal women. Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors. Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types. METHODS: We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation. Clinico-genomic data from SCCOHT and SMARCA4-DUS cohorts were retrospectively extracted from the archives of a large CLIA-certified reference molecular laboratory. RESULTS: We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment. Retrospective comparative analysis of large SCCOHT (n = 48) and SMARCA4-DUS (n = 17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients. CONCLUSIONS: Growing understanding of the role SMARCA4 plays in the pathogenesis of these rare cancers may inform recommended genetic testing and counseling in families with these tumor types.
Assuntos
Carcinoma de Células Pequenas/genética , DNA Helicases/genética , Mutação em Linhagem Germinativa , Hipercalcemia/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Sarcoma/genética , Fatores de Transcrição/genética , Neoplasias Uterinas/genética , Adulto , Carcinoma de Células Pequenas/patologia , Carcinoma de Células Pequenas/terapia , Diferenciação Celular/fisiologia , Estudos de Coortes , DNA Helicases/deficiência , Feminino , Humanos , Hipercalcemia/patologia , Hipercalcemia/terapia , Pessoa de Meia-Idade , Proteínas Nucleares/deficiência , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma/terapia , Fatores de Transcrição/deficiência , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapiaRESUMO
We report the case of a 22-year-old patient with acute abdominopelvic pain. The diagnosis of hypercalcemic small cell carcinoma (SCCOHT)/ovarian rhabdoid tumor has been made. Small cell carcinoma of hypercalcemic type is a rare and aggressive tumor that occurs in young women. The diagnosis of this tumor and the management must be rapid in view of its aggressiveness. Through this observation, we specify the epidemiological, diagnostic, molecular aspects and discussions about its name.
Assuntos
Carcinoma de Células Pequenas/secundário , Neoplasias Primárias Múltiplas/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Tumor Rabdoide/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma de Células Pequenas/química , Carcinoma de Células Pequenas/epidemiologia , Carcinoma de Células Pequenas/genética , Terapia Combinada , DNA Helicases/genética , Diagnóstico Diferencial , Evolução Fatal , Feminino , Heterozigoto , Humanos , Hipercalcemia/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Proteínas de Neoplasias/genética , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/química , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Síndromes Paraneoplásicas/etiologia , Neoplasias Peritoneais/cirurgia , Mutação Puntual , Tumor Rabdoide/química , Tumor Rabdoide/epidemiologia , Tumor Rabdoide/genética , Sarcoma de Ewing/diagnóstico , Fatores de Transcrição/genética , Adulto JovemRESUMO
Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodelling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodelling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumour samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry, with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis, and neuron-like differentiation. EZH2 inhibitors suppressed tumour growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Carcinoma de Células Pequenas/enzimologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Hipercalcemia/enzimologia , Neoplasias Ovarianas/enzimologia , Animais , Apoptose/fisiologia , Carcinoma Epitelial do Ovário , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , DNA Helicases/deficiência , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Histona Metiltransferases , Humanos , Transplante de Neoplasias , Neoplasias Epiteliais e Glandulares/enzimologia , Proteínas Nucleares/deficiência , Fatores de Transcrição/deficiência , Transplante Heterólogo , Células Tumorais Cultivadas , Regulação para CimaRESUMO
SMARCA4 chromatin remodelling factor is mutated in 11% of Coffin-Siris syndrome (CSS) patients and in almost all small-cell carcinoma of the ovary hypercalcaemic type (SCCOHT) tumours. Missense mutations with gain-of-function or dominant-negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole-exome sequencing to study a 15-year-old patient with mild CSS who concomitantly developed SCCOHT at age 13 years. Interestingly, our patient also showed congenital microphthalmia, which has never previously been reported in CSS patients. We detected a de novo germline heterozygous nonsense mutation in exon 19 of SMARCA4 (c.2935C > T;p.Arg979*), and a somatic frameshift mutation in exon 6 (c.1236_1236delC;p.Gln413Argfs*88), causing complete loss of SMARCA4 immunostaining in the tumour. The immunohistochemical findings are supported by the observation that the c.2935C > T mutant transcript was detected by reverse transcription polymerase chain reaction at a much lower level than the wild-type allele in whole blood and the lymphoblastoid cell line of the proband, confirming nonsense-mediated mRNA decay. Accordingly, immunoblotting demonstrated that there was approximately half the amount of SMARCA4 protein in the proband's cells as in controls. This study suggests that SMARCA4 constitutional mutations associated with CSS are not necessarily non-truncating, and that haploinsufficiency may explain milder CSS phenotypes, as previously reported for haploinsufficient ARID1B. In addition, our case supports the dual role of chromatin remodellers in developmental disorders and cancer, as well as the involvement of SMARCA4 in microphthalmia, confirming previous findings in mouse models and the DECIPHER database. Finally, we speculate that mild CSS might be under-recognized in a proportion of SCCOHT patients harbouring SMARCA4 mutations. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Assuntos
Anormalidades Múltiplas/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Pequenas/genética , Códon sem Sentido , DNA Helicases/genética , Face/anormalidades , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Hipercalcemia/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Microftalmia/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/metabolismo , Adolescente , Biomarcadores Tumorais/análise , Western Blotting , Carcinoma de Células Pequenas/química , Carcinoma de Células Pequenas/diagnóstico , DNA Helicases/análise , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/metabolismo , Heterozigoto , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/metabolismo , Imuno-Histoquímica , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/metabolismo , Masculino , Micrognatismo/diagnóstico , Micrognatismo/metabolismo , Microftalmia/diagnóstico , Microftalmia/metabolismo , Pessoa de Meia-Idade , Proteínas Nucleares/análise , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico , Linhagem , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/análiseRESUMO
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a very rare and lethal tumor, mostly affecting young women, with aggressive clinical course. It has a worse prognosis in younger women and most of them died within two years of diagnosis. We are reporting a unique case of SCCOHT in a 35 years old, nulliparous lady with primary infertility in which symptomatic hypercalcemia was a presenting feature of her cancer. She was completely healthy before third cycle of IVF. Within two months of her third IVF cycle, she developed SCCOHT with a very rapid and aggressive course of disease and fatal outcome. Patient died within one month of her first symptom presentation (3 months after IVF cycle).
RESUMO
The introduction of new sequencing technologies has resulted in the discovery of commonly mutated genes in uncommon cancers, including non-epithelial ovarian neoplasms and other rare gynaecological tumours, such as cervical embryonal rhabdomyosarcoma. In some of these neoplasms, mutations in certain genes are both frequent and specific enough for the genomic mutations and sometimes their associated protein loss or overexpression to be used as an aid to diagnosis. In this review, we contrast previous gene identification methods with newer ones, and discuss how the new sequencing technologies (collectively referred to as 'next-generation sequencing') have permitted the identification of specific molecular events that characterize several rare gynaecological neoplasms. We highlight the value of using sequencing to complement traditional pathological methods when diagnosing certain tumours, and provide practical advice to pathologists dealing with these neoplasms. We focus on adult granulosa cell tumours (somatic monoallelic mutations in FOXL2), Sertoli-Leydig cell tumours, gynaecological embryonal rhabdomyosarcomas (germline and somatic mutations in DICER1), and small-cell carcinoma of the ovary, hypercalcaemic type (biallelic mutations in SMARCA4). The new genetic findings provided by next-generation sequencing in these uncommon neoplasms have brought these disorders back into focus, and point the way towards new diagnostic, preventive and therapeutic avenues.
Assuntos
Neoplasias dos Genitais Femininos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Feminino , HumanosRESUMO
OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome. METHODS: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data. RESULTS: The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02). CONCLUSIONS: Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.
Assuntos
Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/terapia , Hipercalcemia/genética , Hipercalcemia/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Adolescente , Adulto , Fatores Etários , Carcinoma de Células Pequenas/patologia , Criança , Estudos de Coortes , DNA Helicases/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Hipercalcemia/patologia , Estimativa de Kaplan-Meier , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição/genética , Adulto JovemRESUMO
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young women. SCCOHT has recently been identified as a monogenic disorder caused by germline and/or somatic SMARCA4 mutations. We describe a 15-year-old Caucasian female with a SCCOHT harboring a previously unreported somatic mutation in the SMARCA4 gene (c.1757delA; p.K586.fs) with loss of heterozygosity. No germline mutation was identified. Subsequent immunohistochemical staining confirmed loss of SMARCA4 protein. These molecular findings will aid with SCCOHT diagnosis through immunohistochemical staining for SMARCA4 and in the future may have implications for the management of this disease.
Assuntos
Carcinoma de Células Pequenas/genética , DNA Helicases/genética , Hipercalcemia/genética , Perda de Heterozigosidade , Mutação , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adolescente , Carcinoma de Células Pequenas/patologia , Feminino , Humanos , Hipercalcemia/patologia , Neoplasias Ovarianas/patologiaRESUMO
Small cell carcinoma of the ovary (SCCOHT) is a rare tumor typically affecting young women. It is a highly malignant tumor accompanied with poor prognosis, early relapse and low survival rates. The most significant prognostic factor is stage of the disease. Due to above mentioned factors there are no guidelines for therapy of this rare tumor. We present a case of 22-years-old patient initially treated with antibiotics under diagnosis of pelvic inflammatory disease. Due to persistent mass at left adnexa, she was indicated for diagnostic laparoscopy, converted to laparotomy and left adnexectomy with frozen section revealing unspecified malignant tumor of left ovary. A conservative operation was performed and, after diagnosis of SCCOHT was established, the patient was indicated for adjuvant chemotherapy.
Assuntos
Carcinoma de Células Pequenas/diagnóstico , Hipercalcemia , Neoplasias Ovarianas/diagnóstico , Adulto , Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/terapia , Terapia Combinada , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/terapia , Ovariectomia , UltrassonografiaRESUMO
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive ovarian malignant neoplasm lacking a unified clinical management process. Most patients are diagnosed at an advanced stage and have an extremely poor prognosis with an overall probability of survival less than 10 %. Here, we describe the case of a patient with advanced SCCOHT achieved a survival of over 5 years after receiving multiple cycles of immunotherapy combined with anti-angiogenic therapy or CDK4/6 inhibitors. At the same time, we also summarized the case reports and clinical trials of immunotherapy in SCCOHT.
Assuntos
Carcinoma de Células Pequenas , Hipercalcemia , Imunoterapia , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/tratamento farmacológico , Carcinoma de Células Pequenas/terapia , Carcinoma de Células Pequenas/tratamento farmacológico , Hipercalcemia/terapia , Hipercalcemia/etiologia , Imunoterapia/métodos , Pessoa de Meia-Idade , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and aggressive malignancy that poses a significant clinical challenge due to its grim prognosis. Unfortunately, only three SCCOHT cell lines are currently available for scientific research. In this study, we have successfully established a novel SCCOHT cell line from a recurrent lesion of a SCCOHT patient, named SCCOHT-CH-1. We comprehensively characterized the novel cell line by employing techniques such as morphological observation, CCK-8 assay, Transwell assay, clone formation assay, short tandem repeat sequence (STR) analysis, karyotype analysis, immunohistochemical staining, western blot assay, and xenograft tumor formation assay. SCCOHT-CH-1 cells were small circular and had a unique STR profile. The population-doubling time of SCCOHT-CH-1 was 33.02 h. The cell line showed potential migratory and invasive ability. Compared with another SCCOHT cell line COV434, SCCOHT-CH-1 exhibited higher expression of AKT, VIM, and CCND1. At the same time, SCCOHT-CH-1 has the ability of tumorigenesis in vivo. We also successfully constructed three patient-derived xenograft (PDX) models of SCCOHT, which were pathologically diagnosed to be consistent with the primary tumor, accompanied by loss of SAMRCA4 protein expression. The establishment of SCCOHT-CH-1 cell line and PDX models from Chinese people represent a pivotal step toward unraveling the molecular mechanism of SCCOHT and fostering the development of targeted interventions to tackle this challenging malignancy.
RESUMO
BACKGROUND: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare aggressive ovarian malignancy mainly affecting children, adolescents, and young adults. Since the discovery of mutations in the SMARCA4 gene in 2014, SCCOHT has become the subject of extensive investigation. However, international uniform treatment guidelines for SCCOHT are lacking and the outcome remains poor. The aim of this systematic review is to generate an overview of all reported patients with SCCOHT from 1990 onwards, describing the clinical presentation, genetic characteristics, treatment, and outcome. METHODS: A systematic search was performed in the databases Embase, Medline, Web of Science, and Cochrane for studies that focus on SCCOHT. Patient characteristics and treatment data were extracted from the included studies. Survival was estimated using Kaplan-Meier's methodology. To assess the difference between survival, the log-rank test was used. To quantify the effect of the FIGO stage, the Cox proportional hazard regression model was estimated. The chi-squared test was used to study the association between the FIGO stage and the surgical procedures. RESULTS: Sixty-seven studies describing a total of 306 patients were included. The median patient age was 25 years (range 1-60 years). The patients mostly presented with non-specific symptoms such as abdominal pain and sometimes showed hypercalcemia and elevated CA-125. A great diversity in the diagnostic work-up and therapeutic approaches was reported. The chemotherapy regimens were very diverse, all containing a platinum-based (cisplatin or carboplatin) backbone. Survival was strongly associated with the FIGO stage at diagnosis. CONCLUSIONS: SCCOHT is a rare and aggressive ovarian cancer, with a poor prognosis, and information on adequate treatment for this cancer is lacking. The testing of mutations in SMARCA4 is crucial for an accurate diagnosis and may lead to new treatment options. Harmonization and international collaboration to obtain high-quality data on diagnostic investigations, treatment, and outcome are warranted to be able to develop international treatment guidelines to improve the survival chances of young women with SCCOHT.
RESUMO
â¢Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare neoplasm that mostly affects young women.â¢The chances of future fertility in women are limited due to the aggressive nature of SCCOHT and need for adjuvant therapy.â¢We report the case of a 26y woman with stage IA SCCOHT who had a successful pregnancy following surgery and chemotherapy.
RESUMO
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 reexpression. BRG1 reexpression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription-factor-binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant-negative AP-1 cell line, we found that both AP-1 DNA-binding activity and BRG1 reexpression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 reexpression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.
Assuntos
Carcinoma de Células Pequenas/patologia , DNA Helicases/genética , Hipercalcemia/patologia , Proteínas Nucleares/genética , Neoplasias Ovarianas/metabolismo , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/genética , Biomarcadores Tumorais/análise , Carcinoma de Células Pequenas/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , DNA Helicases/metabolismo , Feminino , Humanos , Hipercalcemia/genética , Mutação/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Fator de Transcrição AP-1/genética , Fatores de Transcrição/metabolismoRESUMO
The SWI/SNF (mating type SWItch/Sucrose NonFermentable) chromatin remodeling complexes interact with histones and transcription factors to modulate chromatin structure and control gene expression. These evolutionarily conserved multisubunit protein complexes are involved in regulating many biological functions, such as differentiation and cell proliferation. Genomic studies have revealed frequent mutations of genes encoding multiple subunits of the SWI/SNF complexes in a wide spectrum of cancer types, including gynecologic cancers. These SWI/SNF mutations occur at different stages of tumor development and are restricted to unique histologic types of gynecologic cancers. Thus, SWI/SNF mutations have to function in the appropriate tissue and cell context to promote gynecologic cancer initiation and progression. In this review, we summarize the current knowledge of SWI/SNF mutations in the development of gynecologic cancers to provide insights into both molecular pathogenesis and possible treatment implications for these diseases.